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The dawn of gene therapy

It has been a rocky road, but scientists believe that gene therapy is finally about to live up to the hype

What does gene therapy consist of?

The science is complicated, but the idea behind it is simple and elegant. To cure diseases or improve conditions caused by faults in our genes, scientists inject patients with working versions of those faulty genes – a kind of DNA patch. These supplant the old, defective material, enabling the body’s proteins to start to function normally again. Gene therapy holds the promise of resolving the root causes of a vast array of diseases including blindness, Parkinson’s disease and inherited conditions in children. It’s risky, powerful and expensive medicine, however. “We don’t use gene therapy to treat a toothache,” says Professor Patrick Aubourg of the French National Institute of Health and Medical Research.

How long has the idea of gene therapy been around?

The idea goes back to the 1980s, when doctors and scientists began pinpointing the genetic markers of various diseases and the individual, faulty genes behind them. In 1985, the US National Cancer Institute showed that cells taken from patients with adenosine deaminase (ADA) deficiency (which can cause the serious immune disease SCID) could be corrected in the lab. Early thrilling experiments led newspapers to hail a new generation of “gene doctors” capable of “erasing nature’s mistakes”. Five years later, a four-year-old girl named Ashanti with the same condition underwent the world’s first gene-therapy operation. Her health improved, at least for a time, and a new science was born.

Why has it taken so long to develop?

Because the actual mechanics of the process – getting healthy, properly functioning genes into patients’ cells and either fixing, or replacing, their faulty DNA – is formidably difficult. Scientists and pharmaceutical companies have struggled for two decades to find the right “vectors” to deliver new genes into the body. The early vectors of choice were retroviruses, a family of “clever” viruses, able to inveigle themselves into patients’ DNA. Though these viruses were modified to carry healthy genes, they proved unpredictable. In 1999, an 18-year-old with a liver condition died during a gene therapy trial in the US, and a French SCID trial was halted in 2002 when four children developed leukaemia. One later died. “Five to ten years ago, many people would probably have said that gene therapy has no future,” Alain Fischer, a pioneering French gene therapist, said last year.

Are we overcoming these issues?

Yes. Scientists have not only found more reliable viruses to use, but are making use of vectors which are not viruses at all. Earlier this summer, a promising trial for a new gene therapy treatment for cystic fibrosis (a disease affecting more than 9,000 people in the UK) used fatty molecules known as liposomes to carry the healthy genes into the cell. These “gene guns” are less powerful than other vectors as they don’t integrate with the patient’s DNA (“It is rather inefficient,” admits Prof Eric Alton at Imperial College London), but they’re safer. Hundreds of other trials are also under way using relatively harmless viruses – even previously extinct ones (see box) – that scientists insist are easier to control than their predecessors. “At last, the successes are beginning to be more than the failures,” says Professor Inder Verma of the Salk Institute in La Jolla, California.

Which therapies offer most hope?

Those treating genetic conditions caused by a malfunction in a single gene and where fixing a small number of cells can make a big difference to a patient’s health. Since 2011, there have been successful gene therapy trials for haemophilia; for SCID (the original disease targeted in 1990); and for a range of rare inherited degenerative diseases, particularly in the eye. But in the longer term, the hope is that gene therapy could be used on almost any health problem. It “actually has the potential of addressing almost any disease under the sun”, says Dr Luk Vandenberghe of Harvard University. In 2013 and 2014, US companies alone invested more than $600m in the technology; and there are currently clinical trials on everything from Parkinson’s disease to ovarian cancer and heart disease. Nor are the experiments confined just to the replacement of unhealthy genes.

In what other ways are scientists using gene therapy?

They’re using it in a more general way to bolster our cells and immune systems. The human eye, for example, is subject to a range of disorders involving rhodopsin, a light-sensitive pigment; doctors at the University of Pennsylvania are testing the possibility of replacing a patient’s rhodopsin genes – before they deteriorate – with a new, properly functioning set. Another area of research involves using gene therapy to insert into normal immune cells (“T cells”) proteins that encourage the cells to target cancer. In 2011, two patients were cured of leukaemia in this way. T cells are also important in the treatment of HIV and Aids. Around 10% of people of European descent carry a natural genetic immunity to HIV, and scientists are now looking at how this genetic “mutation” might be inserted into victims of the disease.

When are treatments likely to be commercially available?

Some already are. A gene therapy for cancer was approved in China in 2003, although Western regulators have been more hesitant to approve it. The first gene therapy to be approved in Europe was Glybera – a treatment for a rare metabolic disorder that causes pancreatitis – in 2012; it is expected to go on sale this year at a cost of €1m per patient. A further 12 therapies now in the late stage of clinical development are thought to be close to market. This is the way gene therapies will probably appear over the coming years: highly targeted, hugely expensive, but holding the possibility of a cure for otherwise intractable genetic disorders. For example, blood experts believe that gene therapy will be the treatment of choice for haemophilia within a decade. There have been many years of false dawns for gene therapy, but doctors are beginning to believe that this one is real.

Bringing viruses back from the dead

Using the deviousness of viruses to smuggle healthy genes into our cells may sound creepy and futuristic enough, but researchers at Harvard Medical School have gone a step further: recreating an extinct virus as a possible tool for gene therapy. A big problem with using viruses in the first place is that our bodies are used to fighting them. After a few rounds of treatment, patients can develop “immunity” against their gene therapy and stop the viruses from deploying the healthy genetic code they need into their DNA. So now scientists are looking for viruses that don’t exist any more – and to which our bodies have no resistance.

The team at Harvard and the Swiss Federal Institute of Technology “reconstructed” the ancestor of a modern virus. They used algorithms to work out how the family of adeno-associated viruses (AAVs) – which infect humans and primates – evolved, and then reconstructed “Anc80”, a virus they think is between 2,000 and 200,000 years old. A study in the journal Cell Reports showed that Anc80 has been used with success as a gene therapy vector to treat liver, muscle and retina conditions in mice.

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